The present invention relates to methods for making 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in making such compounds.
Corticosteroids are known to have anti-inflammatory and immunomodulatory properties useful in the treatment of numerous diseases, including autoimmune and inflammatory diseases. However, treatment with corticosteroids may cause undesirable side-effects.
Steroid nitrate ester (ONO2) derivatives have been used as nitric oxide donors to potentially increase the therapeutic actions of and counteract or lessen the side-effects of corticosteroids. For example, U.S. Pat. No. 5,985,862 discloses pharmaceutical compositions having steroid nitrate ester (ONO2) derivatives and their use in treating undesired smooth muscle contractions and inflammatory diseases. The ""862 patent also discloses using nitric acid and acetic acid to form certain steroid nitrate ester derivatives.
WO 98/15568 entitled xe2x80x9cNitrate Esters of Corticoid Compounds and Pharmaceutical Applications Thereofxe2x80x9d relates to steroid-structured compounds having anti-inflammatory, immunodepressive, and angiostatic activities. One of the disclosed synthetic routes includes the use of silver nitrate (AgNO3) in acetonitrile. However, silver nitrate is known to be hazardous and toxic if ingested.
It would be desirable to provide an efficient and low-cost method of making 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivatives without using heavy metal compounds such as silver nitrate.
The present invention relates to methods for making 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in the methods for making such compounds.
In one aspect, a method for making a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
reacting:
(a) a 21-hydroxyalkyl corticosteroid;
(b) a compound of formula (I): 
wherein:
R1 is selected from the group consisting of OH, Cl, Br, F, I, and xe2x80x94OC(O)R10;
m is an integer from 0 to 4;
n is an integer from 0 to 5;
R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and xe2x80x94OR7;
R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and xe2x80x94OR7;
R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and xe2x80x94OR7;
R7 is independently selected at each occurrence from the group consisting of hydrogen, xe2x80x94C(O)R8, and xe2x80x94C(O)NR8R9;
R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl; and
R10 is selected from the group consisting of C1-6 alkyl, C1-6 chloroalkyl, alkoxy-substituted C1-6 alkyl, and aryl; and
(c) a coupling agent or a base; with the proviso that when R1 is OH the coupling agent is used and when R1 is Cl, Br, F, I, or xe2x80x94OC(O)R10 the base is used.
In another aspect of the invention, a two-step method for producing a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II): 
with acetic anhydride and nitric acid to form a compound of formula (IA): 
and
(b) reacting the compound of formula (IA) with a 21-hydroxyalkyl corticosteroid and a coupling agent to produce a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R2-R6 are as defined above.
In yet another aspect, a three-step method for producing a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II): 
with acetic anhydride and nitric acid to form a compound of formula (IA): 
(b) reacting the compound of formula (IA) with a halogenating agent to form a compound of formula (IB): 
wherein X is selected from the group consisting of Cl, Br, F, and I; and
(c) reacting the compound of formula (IB) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R2-R6 are as defined above.
In a further aspect, another three-step method for producing a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is provided comprising:
(a) reacting a compound of formula (II): 
with acetic anhydride and nitric acid to form a compound of formula (IA): 
(b) reacting the compound of formula (IA) with an acid anhydride or an acid chloride to form a compound of formula (IC): 
and
(c) reacting the compound of formula (IC) with a 21-hydroxyalkyl corticosteroid and a base to produce a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative; wherein m, n, and R2-R6, and R10 are as defined above.
In yet a further aspect, the present invention provides intermediates of formula (I) useful in the methods for making 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivatives as well as processes for making such intermediates.
The present invention relates to methods for making 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivatives and also relates to intermediates useful in the methods for making such compounds. Prior to describing this invention in further detail, however, the following terms will first be defined.
Definitions:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a branched or straight hydrocarbon group having the general formula CnH2n+1, where n is an integer equal to or greater than 1.
xe2x80x9cC1-6 alkylxe2x80x9d means an alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, t-butyl, and the like.
xe2x80x9cAminoxe2x80x9d refers to the group xe2x80x94NH2.
xe2x80x9cHydroxyxe2x80x9d refers to the group xe2x80x94OH.
xe2x80x9cThioalkylxe2x80x9d refers to the group xe2x80x94Sxe2x80x94(C1-6 alkyl).
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x94Oxe2x80x94(C1-6 alkyl), which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, and the like.
xe2x80x9cSubstituted aminoxe2x80x9d means an amino group in which one or both of the hydrogens are independently replaced with a C1-6 alkyl group, hydroxy, an alkoxy group, or a thioalkyl group.
xe2x80x9cHalogenxe2x80x9d means chlorine (Cl), bromine (Br), iodine (1), or fluorine (F).
xe2x80x9cC1-6 haloalkylxe2x80x9d means a C1-6 alkyl group in which one or more of the hydrogens are independently replaced with a halogen.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinione).
xe2x80x9cC1-6 alkylaminoxe2x80x9d means a C1-6 alkyl group in which one or more of the hydrogens are independently replaced with an amino group.
xe2x80x9cC1-6 substituted alkylaminoxe2x80x9d means a C1-6 alkyl group in which one or more of the hydrogens are independently replaced with a substituted amino group.
xe2x80x9c21-hydroxy corticosteroidxe2x80x9d means any synthetic or naturally-occurring corticosteroid having a hydroxy group attached to the carbon in position 21. Corticosteroids include glucocorticoids and mineralocorticoids. Examples of 21-hydroxy corticosteroids include, but are not limited to, alclometasone, aldosterone, beclomethasone, betamethasone, clocortolone, hydrocortisone, budesonide, cortisone, desoximetasone, desonide, dexamethosone, flucloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone acetonide, fluocortolone, fluprednisolone, flurandrenolide, halometasone, methylprednisolone, paramethasone, prednival, prednylidene, prednisolone, prednisone, triamcinolone, and triamcinolone acetonide.
xe2x80x9c21-hydroxy glucocorticoidxe2x80x9d means any synthetic or naturally-occurring glucocorticoid having a hydroxy group attached to the carbon in position 21. Examples of 21-hydroxy glucocorticoids include, but are not limited to, beclomethasone, methylprednisolone, and paramethasone.
xe2x80x9c21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivativexe2x80x9d means a corticosteroid derivative having a 4-(nitrooxyalkyl)benzoate attached to the carbon in the 21 position of the corticosteroid via an ester linkage with the benzoate as shown and described in formula (IV) below. An example of a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate)] corticosteroid derivative is prednisolone 21-[4xe2x80x2-(nitrooxymethyl)benzoate].
xe2x80x9cAlkoxidexe2x80x9d means a saltlike compound ROM, wherein R is a C1-6 alkyl group and M is a Group I metal such as, for example, sodium or potassium. Alkoxides may be formed by reaction of an alcohol with a Group I metal such as sodium or potassium. Examples of alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, sodium t-butoxide.
xe2x80x9cCarbonatexe2x80x9d means a salt of carbonic acid containing the carbonate ion, CO32xe2x88x92. Examples of carbonates include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate.
xe2x80x9cC1-6 chloroalkylxe2x80x9d means a C1-6 alkyl group in which one or more of the hydrogens are replaced with chlorine.
xe2x80x9cAlkoxy-substituted C1-6 alkylxe2x80x9d means a C1-6 alkyl group in which one or more of the hydrogens are independently replaced with an alkoxy group.
xe2x80x9cAcid anhydridexe2x80x9d means a compound of the formula (Qxe2x80x94C(O))2O, wherein Q is selected from the group consisting of a C1-6 alkyl group, a C1-6 chloroalkyl group, an alkoxy-substituted C1-6 alkyl group, and an aryl group. Examples of acid anhydrides include, but are not limited to, acetic anhydride, chloroacetic anhydride, and dichloroacetic anhydride.
xe2x80x9cAcid chloridexe2x80x9d means a compound of the formula Zxe2x80x94C(O)Cl, wherein Z is selected from the group consisting of a C1-6 alkyl group, a C1-6 chloroalkyl group, an alkoxy-substituted C1-6 alkyl group, and an aryl group. Examples of acid chlorides include, but are not limited to, acetyl chloride, pivaloyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, methoxyacetyl chloride, and benzoyl chloride.
General Reaction Scheme
The general reaction scheme of the invention for producing a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is represented as follows: 
wherein:
Axe2x80x94OH is a 21-hydroxy corticosteroid;
R1 is selected from the group consisting of OH, Cl, Br, F, I, and xe2x80x94OC(O)R10;
m is an integer from 0 to 4;
n is an integer from 0 to 5;
R2 is independently selected at each occurrence from the group consisting of amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino; C1-6 substituted alkylamino, and xe2x80x94OR7;
R3 and R4 are independently selected at each occurrence from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and xe2x80x94OR7;
R5 and R6 are independently selected from the group consisting of hydrogen, amino, substituted amino, halogen, C1-6 alkyl, C1-6 haloalkyl, alkoxy, aryl, C1-6 alkylamino, C1-6 substituted alkylamino, and xe2x80x94OR7;
R7 is independently selected at each occurrence from the group consisting of hydrogen, xe2x80x94C(O)R8, and xe2x80x94C(O)NR8R9;
R8 and R9 are independently selected at each occurrence from the group consisting of hydrogen and C1-6 alkyl; and
R10 is selected from the group consisting of C1-6 alkyl, C1-6 chloroalkyl, alkoxy-substituted C1-6 alkyl, and aryl.
The compound of formula (III) (i.e., Axe2x80x94OH) is preferably a 21-hydroxy glucocorticoid, and is more preferably prednisolone, which is represented by the following formula (IIIA): 
R1 is preferably OH, Cl, or Br, and is more preferably OH. In one preferred embodiment, in the compound of formula (I), R1 is OH, m and n are 0, and R5 and R6 are hydrogen such that the compound of formula (I) is 4-(nitrooxymethyl)benzoic acid.
As shown in the general reaction scheme above, a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative is produced by reacting (a) a compound of formula (III) (i.e., a 21-hydroxy corticosteroid Axe2x80x94OH), (b) a compound of formula (f), and (c) either a coupling agent or a base, depending upon the substituent R1. By way of example, when R1 is OH, (a) a compound of formula (I), (b) a corticosteroid of formula (III), and (c) a suitable coupling agent are reacted. Suitable coupling agents include, but are not limited to, 1,3-diisopropylcarbodiimide, 1,3-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-chloro-1-methylpyridiniurn iodide, and N, N-dimethylformamide neopentylacetal. The preferred coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
By way of further example, when R1 is Br, Cl, F, I, or xe2x80x94OC(O)R10 (a) a compound of formula (I), (b) a corticosteroid of formula (III), and (c) a suitable base are reacted. Suitable bases include, but are not limited to, triethylamine, pyridine, diisopropyl ethylamine, tetramethylguanidine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, alkoxides, and carbonates. The preferred base is triethylamine.
The reaction is preferably carried out in the presence of a catalyst. That is, the compound of formula (I) is preferably reacted with a 21-hydroxy corticosteroid, either a coupling agent or a base, and a suitable catalyst. Suitable catalysts include, but are not limited to, 4-dimethylaminopyridine and N, N-dimethylaniline. The preferred catalyst is 4-dimethylaminopyridine.
The reaction is also preferably carried out in an anhydrous solvent or solvent mixture such as, for example, pyridine, tetrahydrofuran, dimethylformamide, sulfolane, acetone, acetonitrile, ethyl acetate, dioxane, methyl ethyl ketone, ether, methyl t-butyl ether, chloroform, dichloromethane, or mixtures thereof The preferred solvent is acetone.
The reaction is typically carried out in a temperature range from about 0xc2x0 C. to about 50xc2x0 C., and is preferably carried out at about 25xc2x0 C. The reaction is typically carried out for about 15 minutes to about 24 hours, and is preferably carried out from about 5 hours to about 8 hours.
Materials
The 21-hydroxy corticosteroids of formula (III) used in the present invention are generally commercially available or may be obtained according to processes known in the art.
A compound of formula (I) above may be synthesized in one or two steps, depending upon the desired R1 group of the compound (wherein R1 is selected from the group consisting of OH, Cl, Br, F, I, and xe2x80x94OC(O)R10). The following synthetic scheme illustrates the one or two steps needed to produce a compound of formula (I) wherein R1 is OH, Cl, Br, F, or I: 
wherein:
X is selected from the group consisting of Cl, Br, I, or F; and
R2, R3, R4, R5, R6, m, and n are as defined above in the general reaction scheme.
In the first step, the compound of formula (II) is reacted with nitric acid (HNO3) and acetic anhydride (Ac2O) to form the nitroester acid compound of formula (IA). This first step generates a compound of formula (I) in the general reaction scheme above wherein R1 is OH. This reaction is typically carried out in a temperature range from about xe2x88x9250xc2x0 C. to about 0xc2x0 C., and is preferably carried out from about xe2x88x9230xc2x0 C. to about xe2x88x9210xc2x0 C. The reaction is typically carried out for about 1 minute to about 24 hours, and is preferably carried out for about 1 hour to about 3 hours.
In order to form a compound of formula (I) in the general reaction scheme above wherein R1 is Cl, Br, I, or F (i.e., R1 is X), the second step must be carried out. When R1 is Cl, Br, I, or F in the compound of formula (I) (i.e., when X is Cl, Br, I, or F in the compound of formula (IB)), the compound of formula (IA) is halogenated with a suitable halogenating agent to form the acid halide of formula (IB). Suitable halogenating agents include, but are not limited to, the following: chlorinating agentsxe2x80x94thionyl chloride, N-chlorosuccinimide, oxalyl chloride, chlorine, potassium pentachloride, and potassium trichloride; brominating agentsxe2x80x94N-bromosuccinimide, bromine, potassium tribromide, potassium pentabromide, and oxalyl bromide; fluorinating agentsxe2x80x94potassium fluoride, polybydrogen fluoride-pyridine, diethylaminosulfurtrifluoride, hydrogen fluoride, and cyanuric fluoride; iodinating agentsxe2x80x94N-iodosuccinimide and iodine. The reaction is typically carried in a temperature range from about xe2x88x9210xc2x0 C. to about 30xc2x0 C., and is preferably carried out in a temperature range from about 0xc2x0 C. to about 5xc2x0 C. The reaction is typically carried out for about 1 minute to about 24 hours, and is preferably carried out for about 30 minutes.
In order to form a compound of formula (I) in the general reaction scheme above wherein R1 is xe2x80x94OC(O)R10, an alternate second step must be carried out. The following synthetic scheme illustrates the first step described above and the alternate second step: 
wherein:
R2, R3, R4, R5, R6, R10, m, and n are as defined above in the general reaction scheme.
After performing the first step as described above, the compound of formula (IA) is reacted with a suitable acid anhydride or a suitable acid halide to form the compound of formula (IC). Suitable acid anhydrides include, but are not limited to, acetic anhydride, chloroacetic anhydride, and dichloroacetic anhydride. Suitable acid chlorides include, but are not limited to, acetyl chloride, pivaloyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, methoxyacetyl chloride, and benzoyl chloride. The reaction is typically carried out in a temperature range from about xe2x88x9210xc2x0 C. to about 30xc2x0 C., and is preferably carried out in a temperature range from about 0xc2x0 C. to about 5xc2x0 C. The reaction is typically carried out for about 1 minute to about 24 hours, and is preferably carried out for about 30 minutes.
Illustrative Embodiments
In one aspect of the invention and as discussed above in the general reaction scheme, a one-step method is used to produce a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative. As discussed above, the method comprises reacting (a) a compound of formula (III), (b) a compound of formula (I), and (c) either a coupling agent (when R1 is OH in the compound of formula (I)) or a base (when R1 is Cl, Br, F, I, or xe2x80x94OC(O)R10 in the compound of formula (I)). In a preferred embodiment, the compound of formula (III) is prednisolone and, in formulas (I) and (IV), R1 is OH, m and n are 0, and R5 and R6 are hydrogen such that the compounds of formulas (I) and (IV) are respectively 4-(nitrooxymethyl)benzoic acid and prednisolone 21-[(4xe2x80x2-(nitrooxymethyl)benzoate]. Prednisolone 21-[(4xe2x80x2-(nitrooxymethyl)benzoate] is shown below as formula (IVA): 
In another aspect, a two-step method is used wherein a compound of formula (II) is reacted with nitric acid and acetic anhydride to form a nitroester acid of compound (IA). The compound of formula (IA) is reacted with a 21-hydroxy corticosteroid (the compound of formula (III)) and a coupling agent to form a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative of formula (IV). The synthetic scheme is shown as follows: 
In a preferred embodiment, the 21-hydroxy corticosteroid of formula (I) is prednisolone and, in formulas (II), (IA), and (IV), m and n are 0 and R5 and R6 are hydrogen such that the compounds of formulas (II), (IA), and (IV) are respectively 4-(hydroxymethyl)benzoic acid, 4-(nitrooxymethyl)benzoic acid, and prednisolone 21-[(4xe2x80x2-(nitrooxymethyl)benzoate].
In yet another aspect, a three-step method is used to generate a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative. A compound of formula (II) is reacted with nitric acid and acetic anhydride to form a nitroester acid of compound (IA). The compound of formula (IA) is then halogenated with a suitable halogenating agent to form an acid halide of formula (IB). The acid halide of formula (IB) is then reacted with a 21-hydroxy corticosteroid (the compound of formula (III)) and a base to form a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative of formula (IV). The synthetic scheme is shown as follows: 
In a preferred embodiment, the 21-hydroxy corticosteroid of formula (III) is prednisolone and, in formulas (II), (IA), (IB), and (IV), m and n are 0, R5 and R6 are hydrogen, and, in formula (IB), X is Cl or Br such that the compounds of formulas (II), (LA), (IB), and (IV) are respectively 4-(hydroxymethyl)benzoic acid, 4-(nitrooxymethyl)benzoic acid, 4-(nitrooxymethyl)benzoyl chloride or 4-(nitrooxymethyl)benzoyl bromide, and prednisolone 21-[(4xe2x80x2-(nitrooxymethyl)benzoate].
In a further aspect, another three-step method is used to generate a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative. A compound of formula (II) is reacted with nitric acid and acetic anhydride to form a nitroester acid of compound (IA). The compound of formula (IA) is then reacted with a suitable acid anhydride or a suitable acid chloride to form a compound of formula (IC). The compound of formula (IC) is then reacted with a 21-hydroxy corticosteroid (the compound of formula (III)) and a base to form a 21-[4xe2x80x2-(nitrooxyalkyl)benzoate] corticosteroid derivative of formula (IV). The synthetic scheme is shown as follows: 
In a preferred embodiment, the 21 hydroxy corticosteroid of formula (III) is prednisolone and, in formulas (ID), (IA), (IC), and (IV), m and n are 0 and R5 and R6 are hydrogen such that the compounds of formulas (II), (IA), and (m) are respectively 4-(hydroxymethyl)benzoic acid, 4-(nitrooxymethyl)benzoic acid, and prednisolone 21-[(4xe2x80x2-(nitrooxymethyl)benzoate].
Suitable and/or preferred coupling agents, bases, halogenating agents, acid anhydrides, and acid chlorides as well as other suitable and/or preferred 21-hydroxy corticosteroids and compound substituents for each of these aspects of the invention are described above in the general reaction scheme and in the description of the materials.